The explicit goal of the studies described in this proposal is to examine a possible role of the brain metabolites quinolinic acid (QUIN) and kynurenic acid (KYNA) in the pathogenesis of seizure disorders. Both an excess QUIN or a deficiency of KYNA can be envisioned to directly precipitate epileptic phenomena in man. Using a novel brain microdialysis system, extracellular concentrations of QUIN and KYNA will be measured in the hippocampus under various experimental conditions including the application of drugs known to affect QUIN metabolism. EEG records will be obtained simultaneously and related to chemical changes. Experiments will involve the use of a strain of genetically epilepsy prone rats, kindled rats and the examination of effects of a novel anticonvulsant, MK-801, which has been shown to block the convulsive and neurodegenerative effects of QUIN. In parallel experiments, enzymes of the kynurenine pathway, which are responsible for the metabolism of both QUIN and KYNA, will be scrutinized using biochemical and immunocytochemical techniques. Using largely identical methodologies, surgical samples from human epileptic brains will be investigated. The information gathered from animal experiments will be used for a comparison with the situation in the pathologic situation in humans. Thus, upon completion of the work proposed in this application, it should be possible to realistically evaluate if and how a dysfunction of the brain's QUIN and/or KYNA system can contribute to the occurrence of seizure disorders in clinical situations.